Use of angiotensin II receptor antagonists for treating acute myocardial infarction

ABSTRACT

The invention relates to the use of an angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of acute MI and for the secondary prevention of acute MI.

[0001] The enzyme cascade of the renin-angiotensin system (RAS)comprises a series of biochemical events and, as is well known, thereare a variety of approaches for using regulatory intervention to open uptreatment possibilities, for example treatment of hypertension.

[0002] Angiotensinogen, an α2-macroglycoprotein, is cleaved by theenzyme renin into the decapeptide angiotensin I, which is itself onlyvery slightly active biologically. In the next step of the cascade, twofurther amino acids are cleaved off by the action of the enzymeangiotensin converting enzyme (ACE), which is mainly bound in theendothelium, with the formation of angiotensin II. The latter isregarded as being one of the most powerful natural vasconstrictors.

[0003] The vasoconstrictive effects of angiotensin II are brought aboutby its action on the smooth muscle cells, and by stimulating formationof the adrenergic hormones adrenaline and noradrenaline and byincreasing the activity of the sympathetic nervous system due to theformation of noradrenaline. In addition angiotensin II affects theelectrolyte balance, generating, for example, antinatriuretic andantidiuretic effects in the kidney, and consequently promotes release ofthe peptide vasopressin from the pituitary, on the one hand, and ofaldosterone from the adrenal glomerulosa, on the other. All theseeffects play an important role in blood pressure regulation.

[0004] Angiotensin II interacts with specific receptors on the surfaceof the target cells. Success has by now been achieved in identifyingreceptor subtypes which are, for example, designated AT₁ receptors andAT₂ receptors. Recently, considerable efforts have been made to identifythe substances which bind selectively to the AT₁ receptor. These activecompounds are called angiotensin II antagonists or angiotensin IIreceptor blockers. As a consequence of the inhibition of the AT₁receptor, these antagonists can, for example, be employed asantihypertensives or for treating congestive heart failure.

[0005] Ischaemic Heart Disease—Acute Myocardial Infarction

[0006] Ischaemic heart disease is the leading cause of death inindustrialised countries. The management of ischaemic heart diseaseessentially relies upon one of three strategies, comprising medicaltherapy, percutaneous transluminal procedures, such as coronaryangioplasty and atherectomy, and coronary artery bypass grafting.Although medical treatment remains the mainstay of anti-ischaemictherapy, many patients undergo additional, invasive therapy in anattempt to restore coronary blood flow. However, there is increasinglyintense discussion regarding not only the relative merits of thesetherapeutic approaches but also the point within the management ofischaemic heart disease at which they should be applied and the type ofpatient for which each is more appropriate.

[0007] Acute myocardial infarction (MI) strikes the majority ofsufferers without prior warning and in the absence of clinicallydetectable predisposing risk factors (Braunwald E. Heart Disease—aTextbook of Cardiovascular Medicine. 1997). When patients come to theintensive unit in a hospital showing symptoms of acute MI, the diagnosisfor acute MI requires that the patients must have

[0008] (1) an increase in the plasma concentration of cardiac enzymesand

[0009] (2) either a typical clinical presentation and/or typical ECGchanges.

[0010] Either of the following parameters will fulfill the requirementfor an increase in cardiac enzymes:

[0011] Total creatine-kinase (CK) at least 2 times the upper limit ofthe normal range, or

[0012] CK-MB (muscle-brain) above the upper limit of the normal rangeand at least 5% of the normal CK.

[0013] If total CK or CK-MB is not available, the following will beaccepted in the fulfillment of the criteria for acute MI:

[0014] Troponin T at least 3 times the upper limit of the normal range;

[0015] Troponin I at least 3 times the upper limit of the normal range.

[0016] The use of Troponin T as a serum marker for MI is disclosed in V.V. Murthy and A. Karmen, J. Clin. Labor. Analys. 11: 125-128 (1997). Theanalytical performance and clinical utility if a sensitive immunoassayfor determination of cardiac Troponin I can be taken from E. Davies etal. Clin. Biochem. 30: 479-490 (1997).

[0017] Typical ECG changes include evolving ST-segment or T-wave changesin two or more contiguous ECG leads, the development of new pathologicalQ/QS waves in two or more contiguous ECG leads, or the development ofnew left bundle branch block.

[0018] Secondary prevention, namely the implementation of therapy topostpone further coronary events thus continues to remain the major goalof prophylactic drug therapy in these patients.

[0019] Survivors of acute MI are at moderate risk of recurrentinfarction or cardiac death. Morbidity and mortality following an MI maybe related to arrhythmias, to left ventricular dysfunction, and torecurrent MI. Aspirin is used for secondary prevention in survivors ofMI. Because aspirin had a significant protective effect in secondaryprevention of vascular disease, the possible benefit of aspirin inprimary prevention has also been tested. However, several studies haveshown that only a limited percent of the population at risk reallybenefits from aspirin therapy. For primary prevention, for instance,aspirin should be considered only in men over the age of 50 withuncontrolled risk factors for the development of coronary events (CairnsJ A, Lewis H D, Meade T W, Sutton G C, Theroux P. Antithrombotic agentsin coronary artery disease. Chest 108 (supp4):3805, 1995).

[0020] Secondary Prevention of Acute Myocardial Infarction

[0021] The concept of secondary prevention of reinfarction and deathafter recovery from an MI has been actively investigated for severaldecades. Problems in proving the efficacy of various interventions havebeen related both to the ineffectiveness of certain strategies and tothe difficulty in proving a benefit as mortality and morbidity haveimproved following MI. Although secondary prevention drug trialsgenerally have tested one form of therapy against placebo in an attemptto demonstrate a benefit of that therapy, the physician must rememberthat disciplined clinical care of the individual patients is far moreimportant than rote use of an agent found beneficial in the latest drugtrial.

[0022] Primary & Secondary Prevention—Epidemiological

[0023] From an epidemiological standpoint, primary prevention is theprotection of health by personal and community-wide effects such aspreserving good nutritional status, physical fitness and emotionalwell-being. Primary prevention includes general health promotion andspecific protective measures. It can also be defined as prevention ofdisease by altering susceptibility or reducing exposure for susceptibleindividuals. It is difficult to see how the administration of theangiotensin II antagonist losartan, for example, could be viewed as ameasure to promote general health. It would imply administering anangiotensin II antagonist to the population at large, with the—extremelydifficult to quantify—aim of avoiding a MI in part of that population.Secondary prevention, on the other hand, includes all measures availableto individuals and populations for the early detection and prompt andeffective intervention to correct departures from good health. In short,secondary prevention aims to reduce prevalence by shortening theduration.

[0024] ACE inhibitors have been used for secondary prevention inpatients with post-MI, i.e. the use of ACE inhibitors when the patientsuffers his/her FIRST MI can PREVENT further complications related tothe initial event and thus improve survival.

[0025] The development of the AT₁ receptor antagonists provides inaddition to the ACE inhibitors a new, more specific pharmacological toolto inhibit the renin-angiotensin cascade. However, there aredistinguishing features between AT₁ receptor antagonists and ACEinhibitors. One is manifested by the concomitant potentiation ofbradykinin produced by ACE inhibitors, since the kinase II andconverting enzyme are one in the same. The bradykinin related mechanismmediated through nitric oxide, prostaglandins, and endothelially derivedhyper-polaring factor may be responsible for a different clinical effectof ACE inhibitors. Furthermore, the effect of the AT₂ is not yet clear,as an inhibition of the AT₁ receptor leads to an incease of AT₂.

[0026] Treatment, on the other hand, implies implementingmeasures—changes in life-style, specific drugs such as antibiotics—whichcan modify the course of the disease (such as administering angiotensinconverting enzyme inhibitors to patients with congestive heart failurein order to prolong their survival) and/or make the cause of the diseasedisappear. Once the acute MI has been diagnosed, the patient can betreated with a drug which is expected to—decrease his/her mortality rateand—improve short- and long-term prognosis. The rationale behindTREATING patients with an acute MI e.g. with the angiotensin IIantagonist valsartan rests on preliminary preclinical scientific workswhich have shown that the administration of the compound does reduce thesize of the MI, which, through its impact on left ventricular function,is one of the main determinants of survival.

[0027] The aim of the present invention is to provide a therapeuticapproach for the treatment of acute MI and for the secondary preventionof acute MI.

[0028] It has surprisingly been found that angiotensin II receptorantagonists may be used for the treatment of acute MI and for thesecondary prevention of acute MI.

[0029] This beneficial effect can be demonstrated by carrying out studycomparing the efficacy of short-term or long-term application of atherapeutically effective angiotensin II antagonist to an established(recognised) therapy for this indication. Corresponding studies are, forexample, designed by evaluating two parallel groups of patients inprospective multinational, multicenter, double-blind, randomized,actively controlled clinical study having statistical relevance. Thefirst group comprises a population having a high risk of be susceptibleto acute MI, e.g. exhibiting corresponding risk factors, like stress,high blood pressure diabetes, high body weight, family history, etc.,which is treated with a therapeutically effective amount of anangiotensin II receptor antagonist, while the second group likewisecomprises population having likewise a high risk of being susceptible toacute MI, however, treated with an angiotensin converting enzymeinhibitor, such as captopril. The duration of such studies is variableand depends upon achieving a pre-specified number or primary endpoints.For example, such study duration may normally be at least 4 yearsincluding 18 months of enrollment, but may also be shorter. All data andsafety are monitored by an independent monitoring board performinganalyses at timepoints during the study.

[0030] In order to fulfill the criteria of acute MI (cf. above),

[0031] (1) all patients must have an increase in the plasmaconcentration of cardiac enzymes, such as the total creatine-kinase (CK)to at least twice the upper limit of the normal range or the CK-MB isabove the upper limit of the normal range and at least 5% of the totalCK, and

[0032] (2) all patients must have either a typical clinical presentationand/or typical ECG changes, e.g. including evolving ST-segment or T-wavechanges in two or more contiguous ECG leads or include the developmentof the new bundle branch block.

[0033] It can thus be proven that a long-term application with anangiontensin II receptor antagonist can be used for the treatment ofacute MI and for the secondary prevention of acute MI.

[0034] The invention provides a pharmaceutical preparation treatment ofacute MI and for the secondary prevention of acute MI, which comprisesan AT₁ receptor antagonist or a pharmaceutically acceptable saltthereof, either alone or in combination with other accepted treatments(active ingredients) of the acute and chronic phases of MI, such as, forinstance, ACEIs, beta blockers, aspirin, etc., for the treatment ofacute MI, especially in the population at large (including high riskpatients).

[0035] Preferred other accepted treatments (active ingredients) of theacute and chronic phases of MI to be used in a combination with AT₁receptor antagonists are ACE inhibitors, including but not limited to amember of the group consisting of alacepril, benazepril, benazeprilat,captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat,fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril,ramipril, spirapril, temocapril, and trandolapril.

[0036] A combined pharmaceutical preparation for simultaneous, separateor sequential use for the treatment of acute MI and also for thesecondary prevention of acute MI comprising an AT₁ receptor blocker andan other accepted treatment of the acute and chronic phases of MI whichmay be used for such treatment, e.g. selected from the group consistingof an ACE inhibitor, a beta-blocker and aspirin, in each case in a unitdosage form, in admixture with a pharmaceutically acceptable carrier.

[0037] A pharmaceutical combination for the treatment of acute MI andfor the secondary prevention of acute MI comprising an AT₁ receptorblocker and an other accepted active ingredient for the treatment ofacute and chronic phases of myocardial infarction, e.g. selected fromthe group consisting of an ACE inhibitor, a beta-blocker and aspirin,or, in each case, a pharmaceutically acceptable salt thereof inadmixture with a pharmaceutically acceptable carrier.

[0038] All the more surprising is the experimental finding that thecombined administration results not only in a beneficial, especially acomplementary and synergistic, therapeutic effect but also in additionalbenefits resulting from combined treatment such as a surprisingprolongation of efficacy, a broader variety of therapeutic treatment andsurprising beneficial effects on diseases and conditions associated withacute MI.

[0039] Further benefits are that lower doses of the individual drugs tobe combined according to the present invention can be used to reduce thedosage, for example, that the dosages need not only often be smaller butare also applied less frequently, or can be used in order to diminishthe incidence of side effects. This is in accordance with the desiresand requirements of the patients to be treated.

[0040] The invention also provides the use of an angiotensin II receptorantagonist or a pharmaceutically acceptable salt thereof, either aloneor in combination with other accepted treatments of the acute andchronic phases of MI, such as, for instance, ACEIs, beta blockers,aspirin, etc., for the manufacture of a medicament for the treatment ofacute MI and for the secondary prevention of acute MI, especially in thepopulation at large (including high risk patients).

[0041] The invention furthermore provides a method for the treatment ofacute MI and for the secondary prevention of acute MI, especially in thepopulation at large (including high risk patients) which comprisesadministering to a warm-blooded animal, including human, atherapeutically effective amount of an angiotensin II receptorantagonist or a pharmaceutically acceptable salt thereof, either aloneor in combination with other accepted treatments of the acute andchronic phases of MI, such as, for instance, ACEIs, beta blockers,aspirin, etc.

[0042] The invention also provides the use of an angiotensin II receptorantagonist or a pharmaceutically acceptable salt thereof, either aloneor in combination with other accepted treatments of the acute andchronic phases of MI, such as, for instance, ACEIs, beta blockers,aspirin, etc., for the treatment of acute MI, especially in thepopulation at large (including high risk patients).

[0043] Angiotensin II receptor antagonists include compounds havingdiffering structural features. For example, mention may be made of thecompounds which are listed in the European Patent Application having thepublication No. 443983 (EP 443983), in particular in the compound claimsand the final products of the working examples, the subject-matter ofwhich claims is hereby incorporated into the present application byreference to this publication.

[0044] Preference is given to(S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2′(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine[Valsartan] of the formula

[0045] and its pharmaceutically utilizable salts.

[0046] Furthermore, the compounds which are listed in European PatentApplication having the publication No. 253310 (EP 253310), in particularin the compound claims and the final products of the working examples,are hereby incorporated into the present application by reference tothis publication.

[0047] Preference is given to the compound [Losartan] of the followingformula

[0048] and its pharmaceutically utilizable salts.

[0049] Furthermore, the compounds listed in the European PatentApplication having the publication No. 403159 (EP 403159), in particularin the compound claims and the final products of the working examples,are hereby incorporated into the present application by reference tothis publication.

[0050] Preference is given to the compound [Eprosartan] of the followingformula

[0051] and its pharmaceutically utilizable salts.

[0052] Furthermore, the compounds listed in the PCT Patent Applicationhaving the publication No. WO 91/14679, in particular in the compoundclaims and the final products of the working examples, are herebyincorporated into the present application by reference to thispublication.

[0053] Preference is given to the compound [Irbesartan] of the followingformula

[0054] and its pharmaceutically utilizable salts.

[0055] Furthermore, the compounds listed in the European PatentApplication having the publication No. EP 420237 (EP 420237), inparticular in the compound claims and the final products of the workingexamples, are hereby incorporated into the present application byreference to this publication.

[0056] Preference is given to the compound [E-1477] of the followingformula

[0057] and its pharmaceutically utilizable salts.

[0058] Furthermore, the compounds listed in the European PatentApplication having the publication No. 502314 (EP 502314), in particularin the compound claims and the final products of the working examples,are hereby incorporated into the present application by reference tothis publication.

[0059] Preference is given to the compound [Telmisartan] of thefollowing formula

[0060] and its pharmaceutically utilizable salts.

[0061] Furthermore, the compounds listed in the European PatentApplication having the publication No. 459136 (EP 459136), in particularin the compound claims and the final products of the working examples,are hereby incorporated into the present application by reference tothis publication.

[0062] Preference is given to the compound [Candesartan] of thefollowing formula

[0063] and its pharmaceutically utilizable salts.

[0064] Furthermore, the compounds listed in European Patent Applicationhaving the publication No. 504888 (EP 504888), in particular in thecompound claims and the final products of the working examples, arehereby incorporated into the present application by reference to thispublication.

[0065] Preference is given to the compound [SC-52458] of the followingformula

[0066] and its pharmaceutically utilizable salts.

[0067] Furthermore, the compounds listed in the European PatentApplication having the publication No. 514198 (EP 514198), in particularin the compound claims and the final products of the working examples,are hereby incorporated into the present application by reference tothis publication.

[0068] Preference is given to the compound [Saprisartan] of thefollowing formula

[0069] and its pharmaceutically utilizable salts.

[0070] Furthermore, the compounds listed in the European PatentApplication having the publication No. 475206 (EP 475206), in particularin the compound claims and the final products of the working examples,are hereby incorporated into the present application by reference tothis publication.

[0071] Preference is given to the compound of the following formula

[0072] and its pharmaceutically utilizable salts.

[0073] Furthermore, the compounds listed in the PCT Patent Applicationhaving the publication No. WO 93/20816, in particular in the compoundclaims and the final products of the working examples, are herebyincorporated into the present application by reference to thispublication.

[0074] Preference is given to the compound [ZD-8731] of the followingformula

[0075] and its pharmaceutically utilizable salts.

[0076] Angiotensin II receptor antagonists which, for example, possessat least one basic centre can form acid addition salts. These areformed, for example, using strong inorganic acids, such as mineralacids, e.g. sulfuric acid, a phosphoric acid or a hydrohalic acid, usingstrong organic carboxylic acids, such as C₁-C₄alkanecarboxylic acidswhich are unsubstituted or substituted, for example, by halogen, e.g.acetic acid, such as saturated or unsaturated dicarboxylic acids, e.g.oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalicacid, such as hydroxycarboxylic acids, e.g. ascorbic, glycolic, lactic,malic, tartaric or citric acid, such as amino acids, e.g. aspartic orglutamic acid, or such as benzoic acid, or using organic sulfonic acids,such as C₁-C₄alkanesulfonic acids or arylsulfonic acids which areunsubstituted or substituted, for example, by halogen, e.g.methanesulfonic acid or p-toluenesulfonic acid. Examples of suitablesalts with bases are metal salts, such as alkali metal or alkaline earthmetal salts, e.g. sodium, potassium or magnesium salts, or salts withammonia or an organic amine, such as morpholine, thiomorpholine,piperidine, pyrrolidine, a mono-, di- or tri-lower alkyl amine, e.g.ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- ordimethylpropyl-amines, or a mono-, di- or tri-hydroxy lower alkyl amine,e.g. mono-, di- or tri-ethanolamine. Furthermore, corresponding internalsalts can be formed.

[0077] Pharmaceutical preparations are for enteral, such as oral, andalso rectal or parenteral, administration to homeotherms, with thepreparations comprising the pharmacological active compound either aloneor together with customary pharmaceutical auxiliary substances. Forexample, the pharmaceutical preparations consist of from about 0.1% to100%, preferably of from about 1% to about 80%, of the active compound.Pharmaceutical preparations for enteral or parenteral, and also forocular, administration are, for example, in unit dose forms, such ascoated tablets, tablets, capsules or suppositories and also ampoules.These are prepared in a manner which is known per se, for example usingconventional mixing, granulation, coating, solubulizing or lyophilizingprocesses. Thus, pharmaceutical preparations for oral use can beobtained by combining the active compound with solid excipients, ifdesired granulating a mixture which has been obtained, and, if requiredor necessary, processing the mixture or granulate into tablets or coatedtablet cores after having added suitable auxiliary substances.

[0078] The dosage of the active compound can depend on a variety offactors, such as mode of administration, homeothermic species, ageand/or individual condition. Normally, in the case of oraladministration, an approximate daily dose of from about 10 mg to about360 mg, for example in the case of Valsartan e.g. of about 40 mg, 80 mg,160 mg or 320 mg, is to be estimated for a patient.

[0079] A preferred angiotensin II receptor antagonist is valsartan.Valsartan will be supplied in the form of suitable dosage unit form, forexample, a capsule or tablet, and comprising a therapeutically effectiveamount, e.g. from about 20 to about 320 mg, of valsartan which may beapplied to patients in the need to be treated for the secondaryprevention of post-MI. The application of the active ingredient mayoccur up to three times a day, starting e.g. with a daily dose of 20 mgor 40 mg of valsartan, increasing via 80 mg daily and further to 160 mgdaily up to 320 mg daily. Preferably, valsartan is applied twice a daywith a dose of 80 mg or 160 mg, respectively, each. Corresponding dosesmay be taken, for example, in the morning, at mid-day or in the evening.Preferred is b.i.d. administration.

[0080] Preferred dosages for pharmaceutical combinations aretherapeutically effective dosages, especially those which arecommercially available. Especially preferred are low dose combinations.In case of ACE inhibitors, preferred dosage unit forms of ACE inhibitorsare, for example, tablets or capsules comprising e.g. from about 5 mg toabout 20 mg, preferably 5 mg, 10 mg or 20 mg, of benazepril; from about6.5 mg to 100 mg, preferably 6.25 mg, 12.5 mg, 25 mg, 50 mg, 75 mg or100 mg, of captopril; from about 2.5 mg to about 20 mg, preferably 2.5mg, 5 mg, 10 mg or 20 mg, of enalapril; from about 10 mg to about 20 mg,preferably 10 mg or 20 mg, of fosinopril; from about 2.5 mg to about 4mg, preferably 2 mg or 4 mg, of perindopril; from about 5 mg to about 20mg, preferably 5 mg, 10 mg or 20 mg, of quinapril; or from about 1.25 mgto about 5 mg, preferably 1.25 mg, 2.5 mg, or 5 mg, of ramipril.Preferred is t.i.d. administration.

[0081] The following examples illustrate the above-described invention;however, it is not intended to restrict the scope of this invention inany manner.

FORMULATION EXAMPLE 1 Film-coated Tablets

[0082] Composition Components Per Unit (mg) Standards GranulationValsartan [=active ingredient] 80.00 Microcrystalline cellulose/ 54.00NF, Ph. Eur Avicel PH 102 Crospovidone 20.00 NF, Ph. Eur Colloidalanhydrous silica/ 0.75 Ph. Eur/ colloidal silicon dioxide/Aerosil 200 NFMagnesium stearate 2.5 NF, Ph. Eur Blending Colloidal anhydrous silica/0.75 Ph. Eur/ colloidal silicon dioxide/Aerosil 200 NF Magnesiumstearate 2.00 NF, Ph. Eur Coating Purified water*⁾ — DIOLACK pale red00F34899 7.00 Total tablet mass 167.00

[0083] The film-coated tablet is manufactured e.g. as follows:

[0084] A mixture of valsartan, microcrystalline cellulose, crospovidone,part of the colloidal anhydrous silica/colloidal silicondioxide/Aerosile 200, silicon dioxide and magnesium stearate is premixedin a diffusion mixer and then sieve through a screening mill. Theresulting mixture is again pre-mixed in a diffusion mixer, compacted ina roller compacter and then sieve through a screening mill. To theresulting mixture, the rest of the colloidal anhydrous silica/colloidalsilicon dioxide/Aerosile 200 are added and the final blend is made in adiffusion mixer. The whole mixture is compressed in a rotary tablettingmachine and the tabletts are coated with a film by using Diolack palered in a perforated pan.

FORMULATION EXAMPLE 2 Film-coated Tablets

[0085] Composition Components Per Unit (mg) Standards GranulationValsartan [=active ingredient] 160.00 Microcrystalline cellulose/ 108.00NF, Ph. Eur Avicel PH 102 Crospovidone 40.00 NF, Ph. Eur Colloidalanhydrous silica/ 1.50 Ph. Eur/ colloidal silicon dioxide/Aerosil 200 NFMagnesium stearate 5.00 NF, Ph. Eur Blending Colloidal anhydrous silica/1.50 Ph. Eur/ colloidal silicon dioxide/Aerosil 200 NF Magnesiumstearate 4.00 NF, Ph. Eur Coating Opadry Light Brown 00F33172 10.00Total tablet mass 330.00

[0086] The film-coated tablet is manufactured e.g. as described inFormulation Example 1.

FORMULATION EXAMPLE 3 Film-coated Tablets

[0087] Composition Per Components Unit (mg) Standards Core: Internalphase Valsartan 40.00 [=active ingredient] Silica, colloidal anhydrous1.00 Ph. Eur, USP/NF (Colloidal silicon dioxide) [=Glidant] Magnesiumstearate 2.00 USP/NF [=Lubricant] Crospovidone 20.00 Ph. Eur[Disintegrant] Microcrystalline cellulose 124.00 USP/NF [=Binding agent]External phase Silica, colloidal anhydrous, 1.00 Ph. Eur, USP/NF(Colloidal silicon dioxide) [=Glidant] Magnesium stearate 2.00 USP/NF[Lubricant] Film coating Opadry ® brown OOF 16711*⁾ 9.40 PurifiedWater**⁾ — Total tablet mass 199.44

Opadry® Composition

[0088] Approximate % Ingredient Composition Iron oxide, black (C.I. No.77499, E 172) 0.50 Iron oxide, brown (C.I. No. 77499, E 172 0.50 Ironoxide, red (C.I. No. 77491, E 172) 0.50 Iron oxide, yellow (C.I. No.77492, E 172) 0.50 Macrogolum (Ph. Eur) 4.00 Titanium dioxide (C.I. No.77891, E 171) 14.00 Hypromellose (Ph. Eur) 80.00

[0089] The film-coated tablet is manufactured e.g. as described inFormulation Example 1.

FORMULATION EXAMPLE 4 Capsules

[0090] Composition Components Per Unit (mg) Valsartan [=activeingredient] 80.00 Microcrystalline cellulose 25.10 Crospovidone 13.00Povidone 12.50 Magnesium stearate 1.30 Sodium lauryl sulphate 0.60 ShellIron oxide, red 0.123 (C.I. No. 77491, EC No. E 172) Iron oxide, yellow0.123 (C.I. No. 77492, EC No. E 172) Iron oxide, black 0.245 (C.I. No.77499, EC No. E 172) Titanium dioxide 1.540 Gelatin 74.969 Total tabletmass 209.50

[0091] The tablet is manufactured e.g. as follows:

[0092] Granulation/Drying

[0093] Valsartan and microcrystalline cellulose are spray-granulated ina fluidised bed granulator with a granulating solution consisting ofpovidone and sodium lauryl sulphate dissolved in purified water. Thegranulate obtained is dried in a fluidised bed dryer.

[0094] Milling/Blending

[0095] The dried granulate is milled together with crospovidone andmagnesium stearate. The mass is then blended in a conical screw typemixer for approximately 10 minutes.

[0096] Encapsulation

[0097] The empty hard gelatin capsules are filled with the blended bulkgranules under controlled temperature and humidity conditions. The filedcapsules are dedusted, visually inspected, weightchecked and quarantieduntil by Quality assurance department.

FORMULATION EXAMPLE 5 Capsules

[0098] Composition Components Per Unit (mg) Valsartan [=activeingredient] 160.00 Microcrystalline cellulose 50.20 Crospovidone 26.00Povidone 25.00 Magnesium stearate 2.60 Sodium lauryl sulphate 1.20 ShellIron oxide, red 0.123 (C.I. No. 77491, EC No. E 172) Iron oxide, yellow0.123 (C.I. No. 77492, EC No. E 172) Iron oxide, black 0.245 (C.I. No.77499, EC No. E 172) Titanium dioxide 1.540 Gelatin 74.969 Total tabletmass 342.00

[0099] The formulation is manufactured e.g. as described in FormulationExample 4.

FORMULATION EXAMPLE 6 Hard Gelatine Capsule

[0100] Composition Components Per Unit (mg) Valsartan [=activeingredient] 80.00 Sodium laurylsulphate 0.60 Magnesium stearate 1.30Povidone 12.50 Crospovidone 13.00 Microcrystalline cellulose 21.10 Totaltablet mass 130.00

FORMULATION EXAMPLE 7

[0101] A hard gelatin capsule, comprising as active ingredient e.g.(S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2′(1H-tetrazol-5-yl)biphenyl-4-yl-methyl]amine,can be formulated, for example, as follows:

Composition

[0102] (1) valsartan 80.0 mg

[0103] (2) microcrystalline cellulose 110.0 mg

[0104] (3) polyvidone K30 45.2 mg

[0105] (4) sodium lauryl sulfate 1.2 mg

[0106] (5) crospovidone 26.0 mg

[0107] (6) magnesium stearate 2.6 mg

[0108] Components (1) and (2) are granulated with a solution ofcomponents (3) and (4) in water. The components (5) and (6) are added tothe dry granulate and the mixture is filled into size 1 hard gelatincapsules.

1. A method for the secondary prevention of acute MI comprisingadministering a therapeutically effective amount of an angiotensin IIreceptor antagonist or a pharmaceutically acceptable salt thereof to apatient who is asymptomatic with respect to heart failure.
 2. The methodof claim 1 wherein the angiotensin II receptor antagonist is combinedwith a second active ingredient.
 3. (canceled)
 4. The method of claim 1wherein the AT₁-receptor antagonist is selected from the groupconsisting of:

or, in each case, of a pharmaceutically acceptable salt thereof.
 5. Themethod of claim 1 wherein the angiotensin II receptor antagonist isvalsartan of formula

or a pharmaceutically acceptable salt thereof.
 6. The method of claim 2wherein the second active ingredient is selected from the groupconsisting of alacepril, benazepril, benazeprilat, captopril,ceronapril, cilazapril, delapril, enalapril, enaprilat, fosinopril,imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril,spirapril, temocapril, and trandolapril.
 7. The method of claim 6wherein the second active ingredient is captopril.
 8. A pharmaceuticalcombination composition for the secondary prevention of acute MIcomprising an AT₁ receptor blocker and a second active ingredient forthe treatment of acute and chronic phases of myocardial infarctionselected from the group consisting of an ACE inhibitor, a beta-blockerand aspirin, or, in each case, a pharmaceutically acceptable saltthereof in admixture with a pharmaceutically acceptable carrier.
 9. Thepharmaceutical combination composition of claim 8 for simultaneous,separate or sequential use.